Managing Progression – Clinical Management of GIST

Helsinki and Barcelona 2003-Conference Highlights

Charles D. Blanke, M.D., director of gastrointestinal oncology at Oregon Health and Science University (OHSU), Portland, Oregon, USA, discussed the treatment of Gleevec-resistant GIST at the 3rd International Symposium on GIST, in Helsinki. He expanded on his remarks in a subsequent interview.

Question: Could we begin with a brief overview of the issue of drug-resistant GIST?

Dr. Blanke: As the most effective drug therapy for GIST available to date, Gleevec® (Gleevec) has completely changed the way GIST patients are managed and has brought them an unprecedented degree of hope. But we do not believe at this time that it cures the disease, and we are seeing cases of primary resistance—that is, people who do not benefit from Gleevec from the outset. The number of these cases is extremely small—5% to 15%.

A secondary population will either respond to the drug or have complete stabilization of their disease, and then later demonstrate resistance, in the form of tumor growth. Renewed disease activity in Gleevec-treated patients, when it occurs, is commonly seen after about 15 to 18 months of therapy, but of course it can appear at any time. It is important to monitor GIST patients carefully for disease recurrence. We at OHSU, and other experts throughout the United States, recommend seeing a GIST patient every 3 months; obtaining a CT scan every 3 months; and performing blood tests, mainly for toxicity.

Question: When you see a resistant patient, what do you do next?

Dr. Blanke: First, it is important to make sure that what you are seeing truly is disease progression. A massive lesion may become very necrotic and liquefied, and it can actually be larger if a CT scan is obtained at 8 weeks after the start of Gleevec treatment. But this finding can represent cellular death, not growth of cells or proliferation. To confirm progression, a PET scan might be helpful. If the patient’s CT findings worsen but the PET scan shows improvement, then the patient’s GIST is not progressing. On the other hand, if both the CT and PET scans show worsening, then progression probably is occurring. Second, there are different patterns of progression in GIST. Some people’s tumors basically progress everywhere—all the lesions become larger.

The initial line of attack in that setting is an increase in the Gleevec dose if the patient is not already receiving high-dose therapy and the escalation is tolerable. In other cases, the overwhelming proportion of disease sites remain under control with Gleevec—that is, 90%to 95% of the tumors continue to shrink or cease to grow—but one area on the CT scan enlarges. If a patient has what we consider to be one bad clone, the physician should probably think very strongly about whether there is any potential for surgical eradication of that clone, either by surgical resection or radiofrequency ablation.

Question: Would you say, then, that the current options for the Gleevec-treated patient with GIST progression are dose escalation, Sutent and/or excision of growing lesions?

Dr. Blanke: Yes, and the next step should be referral for an experimental trial.

Question: Is there any role for discontinuation of Gleevec?

Dr. Blanke: No. This is an incredibly important point and very different from what we do in other malignancies. There is a large quantity of anecdotal data now indicating that even in cases of GIST progression, stopping Gleevec causes the disease to progress faster. Patients may sicken and die within a couple of weeks. Basically, unless patients are minutes from death or they are tolerating Gleevec very poorly, experts in the United States recommend continuing the drug indefinitely. I would be very reluctant to discontinue the drug. See Stopping Gleevec.

Question: Dosing is another frequently discussed issue. At what dosage should Gleevec therapy be started?

Dr. Blanke: The dosing question stems from 2 studies. There is a US phase III trial and a European phase III trial that have yielded slightly different findings. The US trial, for which a preliminary analysis is available, compared 400 and 800 mg of Gleevec daily for the treatment of GIST and found no difference in response, progression, or survival.

The European trial found a minimal advantage with respect to progression for the 800-mg dose. The data are still preliminary. In my opinion, the evidence does not yet prove that the 800-mg daily dose is better. US physicians strongly advocate starting patients at 400 mg/d and then escalating the dose if the disease progresses. Some European authorities do advocate a higher starting dose.

Question: Suppose the patient is started on Gleevec therapy at 400 mg/d, but the response seems to be suboptimal. Should dose escalation be considered?

Dr. Blanke: It depends on the therapeutic goal. If the physician thinks that with shrinkage the disease might ultimately become resectable, then dose escalation could well be a reasonable step. If there is massive widespread disease, it can be difficult to balance the risk of toxicity against the possible benefit of escalation. I have used this approach for selected patients who wanted to proceed more aggressively with their treatment.

Question: What final thoughts would you want to share with the broad community of your colleagues in oncology?

Dr. Blanke: GIST remains relatively rare in the community, and it is a disease in which treatment experience is particularly valuable. Most of the international experts are very friendly about receiving telephone calls or e-mail messages requesting advice. I would encourage physicians who are caring for GIST patients to contact the research centers if they have any type of question.

UPDATE: On January 26, 2006

Sutent® was approved for patients in the United States. We asked Dr. Blanke several questions about this new option for GIST patients.

Question: What is Sutent and how does its approval change the options for Gleevec-resistant GIST?

Dr. Blanke: Sutent is a oral drug which inhibits several targets potentially important in GIST growth. It is the only drug approved after Gleevec failure. The difficulty will be knowing when to integrate Sutent into the treatment paradigm.

Question: For Gleevec-resistant GIST, should dose-escalation of Gleevec precede therapy with Sutent?

Dr. Blanke: If a patient is on less than 800 milligrams per day, and is tolerating the drug; absolutely. The American and European large-scale studies both showed a substantial proportion of patients will benefit from that simple intervention.

Question: For Gleevec-resistant patients; which should be considered first, Sutent or a clinical trial?

Dr. Blanke: This is a difficult question to answer. Sutent has a proven track record, helping some, but not all patients. One important question would be whether taking Sutent disqualifies the patient from the trial. If so, the trial would have to come first.

Question: Are there some groups of patients that should consider a clinical trial prior to Sutent?

Dr. Blanke: See above. I would not use genetic testing currently to make that decision-the numbers of patients in each genetic group are too small to make a firm decision. On the B2222 Gleevec study, none of the wild-type patients had a remission. That was not true in the much larger US study.

Definite GIST progression? (CT, MRI, PET)

Check histology

Systemic progression

Localized progression

Systemic treatment options

Local treatment options

Continue imatinib
with dose increase
(600-800mg/d)

Surgery
Laser ablation
Radiofrequency ablation

Investigational
new studies

Sutent

Continue imatinib; consider a dose increase if patient is on less than 800 mg per day

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